The blood-brain barrier that exists in all vertebrate brains was discovered in the latter part of the 19th century and the first half of the 20th century. Researchers discovered that dyes injected intravenously into the bloodstream stained all internal organs except the brain and that dyes injected into the cerebrospinal fluid stained cells of the brain but did not enter the bloodstream to stain other internal organs. It was later discovered that the blood-brain barrier was due to the structure of the capillary walls of the brain.
In organs other than the brain, fluid leaks out of capillaries and enters the tissue through pores formed at the junction of adjacent endothelial cells. In the brain, however, endothelial cells of capillaries are intimately fused by intercellular tight junctions. The tight junctions prevent the paracellular leakage of fluid from the capillaries, leaving transcellular flow from the capillary to the brain as the only means for fluid and solutes to enter the brain from the bloodstream.
Among the means of transcellular fluid flow available to other organs of the body, pinocytosis is virtually nonexistent in brain capillaries. Consequently, solutes may enter the brain in one of two ways. In facilitated transport, a specialized carrier or receptor catalyst molecule transports a particular molecule through the endothelial cell wall into the brain. In lipid-mediated transport, small lipid soluble molecules dissolve in and diffuse through the endothelial cell membrane.
While these mechanisms permit the entry into the brain of essential nutrients, the existence of the blood-brain barrier effectively prevents other substances, such as hormones, proteins, certain ions, and drugs, from entering the brain. Although it is normally quite useful to protect the brain from exposure to these substances, the blood-brain barrier also serves to prevent therapeutic or diagnostic agents from reaching the substance of the brain or the cerebrospinal fluid, rendering it difficult to treat or diagnose certain diseases.
Consequently, methods of penetrating the blood-brain barrier so as to permit entry of therapeutic or diagnostic substances have long been sought. Kozarich et al., U.S. Pat. No. 5,686,416, discloses that intravenous injection of certain peptide analogues of bradykinin increase the permeability of the blood-brain barrier to co-administered therapeutic or diagnostic agents. The peptides function by attaching to certain receptors on the surface of brain-blood barrier endothelial cells, which causes the blood-brain barrier to become permeable. As disclosed in Kozarich, only peptides having a particular amino acid sequence adopt the proper conformation to interact with the receptors and increase the permeability of the blood-brain barrier. Kozarich states that the peptides may be administered by several routes, including intravascular, subcutaneous, and intramuscular injection, and by oral, transdermal, intranasal, and inhalation administration. However, in all eleven examples of in vivo treatment with the peptides, only intravascular injections were shown to be effective.
In contrast to Kozarich, U.S. Pat. No. 4,866,042 (Neuwelt) and U.S. Pat. No. 5,059,415 (Neuwelt) disclose the opening of the blood-brain barrier by an osmotic disruption of the blood-brain barrier. According to Neuwelt, the blood-brain barrier is temporarily opened to permit the entry of genetic material and diagnostic imaging agents into the brain by the intraarterial injection of a hyperosmotic sugar, such as mannitol, arabinose, and glucose. The resultant hypertonicity of the blood adjacent to the cells of the blood-brain barrier causes these cells to shrink, leaving gaps between the cells. Compounds within the bloodstream can then enter the brain through these gaps. Neuwelt reports that, in contrast to the normal state in which the blood brain barrier excludes molecules having a molecular weight larger than 180 Daltons, when the blood-brain barrier is opened by osmotic disruption, molecules having a molecular weight of 1,000,000 Daltons can pass.
Naito, A., in European Patent No. 652012A1 and Canadian Patent No. 2,103,339, discloses that certain pure sugars in combination with certain amino acids, when administered orally or intravenously in sufficient quantities, have the ability to effect the entry of other materials across the blood-brain barrier. The disclosure of Naito represents an advance over that of Kozarich in that a peptide having a particular amino acid sequence is not necessary and a workable method of oral administration is disclosed. The disclosure of Naito represents an advance over that of Neuwelt in that intraarterial administration of the hyperosmotic agent is unnecessary in order to cause osmotic disruption of the blood-brain barrier. Rather, as discovered by Naito, the blood-brain barrier can be breached by less invasive methods of hypertonic sugar administration.
The method disclosed by Naito requires a substantial quantity of sugar and amino acid to be utilized. To deliver a therapeutic amount of most materials across the blood-brain barrier, however, an amount of sugar between 0.5 and 10 grams, preferably between 0.5 and 6 grams, and an amount of amino acids between 300 to 2000 mg is required. Consequently, only oral and injection routes of administration were disclosed by Naito as being effective.
The need remains, however, for methods to traverse the blood-brain barrier in patients, both human and animal, in which intravascular and oral administration is impractical, impossible, or otherwise undesirable.
U.S. Pat. No. 5,756,071 (Mattern) discloses that the intranasal administration of certain sex hormones and biogenic amines resulted in a higher concentration in the blood than if these substances were administered perorally. Neurologic symptoms were improved following intranasal administration compared with peroral administration, which improvement was attributed by the inventors to be due probably to easier passage through the blood-brain barrier following pernasal administration.
Mattern does not disclose the facilitated entry across the blood-brain barrier of any substance other than that which is itself administered pernasally.